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At least 757 records · Page 42Linked to original sources
PubMed2004

Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury.

OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects, such as promoting angiogenesis, increasing fibrinolysis, and reducing inflammatory responses, and has shown promise in enhancing recovery in animals with traumatic brain injury (TBI) and stroke. The authors tested the effect of atorvastatin on vascular changes after TBI. METHODS: Male Wistar rats subjected to controlled cortical impact injury were perfused at different time points with fluorescein isothiocyanate (FITC)--conjugated dextran 1 minute before being killed. Spatial memory function had been measured using a Morris Water Maze test at various points before and after TBI. The temporal profile of intravascular thrombosis and vascular changes was measured on brain tissue sections by using a microcomputer imaging device and a laser confocal microscopy. The study revealed the following results. 1) Vessels in the lesion boundary zone and hippocampal CA3 region showed a variety of damage, morphological alterations, reduced perfusion, and intraluminal microthrombin formation. 2) Atorvastatin enhanced FITC-dextran perfusion of vessels and reduced intravascular coagulation. 3) Atorvastatin promoted the restoration of spatial memory function. CONCLUSIONS: These results indicated that atorvastatin warrants investigation as a potential therapeutic drug for TBI.

Animals↗
PubMed2004

Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat.

The effects of raloxifene on acquisition of a delayed matching to position (DMP) T-maze task and on hippocampal acetylcholine release were evaluated and compared with estradiol, to determine whether raloxifene has estrogenic effects on cognitive performance and hippocampal cholinergic activity. Ovariectomized rats received continuous treatment with raloxifene (one of two doses), estradiol, or vehicle for 30 days, followed by behavioral training, and then in vivo microdialysis assessment of basal and potassium-stimulated acetylcholine release. The data show that estradiol significantly enhanced DMP acquisition, whereas raloxifene did not. In contrast, both estradiol and the higher dose of raloxifene significantly increased potassium-stimulated acetylcholine release in the hippocampus. These data suggest that, despite increasing evidence for estrogenic effects of raloxifene in brain, raloxifene does not mimic the effects of estrogen on cognitive performance as assessed by acquisition of a simple spatial memory task in ovariectomized rats.

Acetylcholine↗
PubMed2006

Dissociation of the roles of NMDA receptor and hippocampus in rats' spatial learning: the effects of environmental familiarity and task familiarity.

In this study, we compared the effects of MK-801 and hippocampal lesions on re-training of Morris water maze place task in familiar and novel environments in rats. In Experiment 1, rats were pre-trained with the place task. After acquiring the task, rats were re-trained with the same task in a familiar environment following MK-801 injection, and were then trained with the same task in a novel environment following MK-801 injection. In the familiar environment, MK-801 had no effect, but in the novel environment performance was impaired. In Experiment 2, after the place task training, the hippocampus was lesioned, and rats were re-trained with the same task in the familiar environment then retrained again in the novel environment. Rats showed severe impairment in both environments. These two experiments suggest different functions for NMDA receptors and the hippocampus. The results of Experiment 1 showed that NMDA receptors are not required for utilizing spatial representations but they play an important role in the construction of spatial representations. The results of Experiment 2 show that the hippocampus is necessary for both the utilization of spatial representations already formed and the formation of new spatial representations.

Animals↗
PubMed1997

Effects of a single intraseptal injection of NGF on spatial learning in the water maze.

Male Sprague-Dawley rats given electrolytic lesions of the septum followed by a single intraseptal injection of 5 microg of NGF were trained on a water maze task that assessed their ability to learn the location of a visible platform and the location of platform when it was submerged. Rats with damage to the septum acquired the visible platform version of the task but were significantly impaired in locating the submerged platform. Administration of NGF, however, produced an intermediate ameliorative effect on the measure of latency to find the hidden platform during these trials. In order to determine the relative strength of the place and cue responses learned during the visible and hidden platform training trials, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both a place and cue response. However, both rats with septal damage alone and rats with septal lesions treated with NGF swam directly to the new platform location indicating the relative strength of the cue response. These results support previous findings indicating that a single injection of NGF can produce improvements on a cognitive task, but it may not be doing so by restoring lost spatial functions following septohippocampal damage.

Acetylcholinesterase↗
PubMed1996

The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation.

The alpha-2,8-linked polysialic acid (PSA) modification of the neural cell adhesion molecule (NCAM) modulates morphogenetic cell interactions. PSA is strongly expressed during neural development and generally down-regulated in the adult. However, it remains prominent in some areas of the brain, e.g., the hippocampus. We assayed the functional role(s) of PSA in synaptic plasticity in the hippocampus in two experimental paradigms by removing PSA with endo-neuraminidase NE (endo-N) an enzyme which specifically cleaves alpha-2,8-linked polysialic acid. (1) The acquisition and retention of spatial memory of rats in the Morris water maze, critically dependent on the hippocampus, was significantly impaired after a localized injection of endo-N into the hippocampus, whereas visual and motor capacities were unaffected. (2) Tetanic stimulation of the Schaffer collaterals in endo-N-treated hippocampal slices in vitro failed to elicit LTP and yielded only a short post-tetanic potentiation, but the response returned to control levels within 2 minutes, whereas basal synaptic activity and short-term potentiation were not affected. Our findings suggest that the carbohydrate epitope PSA plays an important role in synaptic plasticity.

Analysis of Variance↗
PubMed2000

Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression.

Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the normal anxiogenic-like effect of restraint stress on the elevated plus maze and displayed absent fear suppression of behavior in a punished drinking test. (ii) A selective impairment of spatial memory acquisition was found in the Morris water maze. Control experiments suggest these traits to be independent. These phenotypic traits were accompanied by an overexpression of prepro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippocampus, a brain structure implicated both in memory processing and stress responses. Data obtained using this unique model support and extend a previously postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.

Animals↗
PubMed2005

Long-term neurotoxicity of chlorpyrifos: spatial learning impairment on repeated acquisition in a water maze.

Organophosphate compounds are cholinesterase inhibitors widely used in agriculture, industry, household products, and even as chemical weapons. Their major mechanism of acute toxic action is the inhibition of acetylcholinesterase, which is responsible for the degradation of the neurotransmitter acetylcholine. An organophosphorus ester-induced chronic neurotoxicity (OPICN) syndrome has been proposed. The OPICN syndrome could result from both long-term exposure to subclinical doses of OPs and after acute poisoning. Development of animal models for the cognitive decline are required and could later help to elucidate the mechanisms involved in this long-term effect on the central nervous system. Previously, we have found performance decrements in a four-trial repeated acquisition spatial task in a water maze. The present study includes two experiments to extend the long-term behavioral effects observed. Rats were injected either once or twice with chlorpyrifos (CPF) and then tested months after in a two-trial repeated acquisition task in a water maze. Our results confirm and extend the long-term behavioral effects of subcutaneous administration of CPF. The two treatments used produced performance decrements that suggest functional central nervous system alterations.

Acetylcholinesterase↗
PubMed2004

Aged neuropeptide Y transgenic rats are resistant to acute stress but maintain spatial and non-spatial learning.

The behavioral phenotype of five-month-old rats overexpressing neuropeptide Y (NPY) has previously been described [Proc Natl Acad Sci USA 97 (2000) 12852]. In this transgenic rat model, there is central overexpression of prepro-NPY mRNA and NPY peptide in the hippocampus and hypothalamus and decreased Y1 binding sites within the hippocampus. These molecular and neurochemical events led to altered anxiety profile and learning abilities in NPY-overexpressing rats. In the present study, anxiety and learning/memory related behaviors were examined in one-year-old NPY-transgenic rats in order to assess any behavioral changes that may have occurred during the aging process. As observed in 5-month-old overexpressing rats, aged NPY-transgenic animals are resistant to acute physical restraint stress measured by the elevated-plus maze and demonstrate anxiolytic-like activity in the open field. However, in contrast to data in young rats, there was no significant difference between aged wildtype and NPY-transgenic animals in relation to spatial and non-spatial memory as indicated by the (allo- and ego-centric) Morris water maze and object recognition test. It would thus appear that the anxiolytic-like profile observed in young NPY-overexpressing rats is maintained in older animals providing further evidence for a role for NPY in anxious behaviors. However, the cognitive deficits observed in young rats do not appear to occur in older animals suggesting the existence of compensatory mechanisms leading to a reversal of the learning deficits noted in younger animals. These results also provide additional evidence for the mechanistic dissociation between anxiety and cognition-related behaviors modulated by NPY.

Adaptation, Psychological↗
PubMed2006

Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress.

Increasing evidences indicate the concurrence and interrelationship of depression and cognitive impairments. The present study was undertaken to investigate the effects of two depressive animal models, learned helplessness (LH) and chronic mild stress (CMS), on the cognitive functions of mice in the Morris water maze task. Our results demonstrated that both LH and CMS significantly decreased the cognitive performance of stressed mice in the water maze task. The escaping latency to the platform was prolonged and the probe test percentage in the platform quadrant was reduced. These two models also increased the plasma corticosterone concentration and decreased the brain derived neurotrophic factor (BDNF) and cAMP-response element-biding protein (CREB) messenger ribonucleic acid (mRNA) levels in hippocampus, which might cause the spatial cognition deficits. Repeated treatment with antidepressant drugs, imipramine (Imi) and fluoxetine (Flu), significantly reduced the plasma corticosterone concentration and enhanced the BDNF and CREB levels. Furthermore, antidepressant treated animals showed an ameliorated cognitive performance compared with the vehicle treated stressed animals. These data suggest that both LH and CMS impair the spatial cognitive function and repeated treatment with antidepressant drugs decreases the prevalence of cognitive impairments induced by these two animal models. Those might in part be attributed to the reduced plasma corticosterone and enhanced hippocampal BDNF and CREB expressions. This study provided a better understanding of molecular mechanisms underlying interactions of depression and cognitive impairments, although animal models used in this study can mimic only some aspects of depression or cognition of human.

Animals↗
PubMed1991

Paternal alcohol consumption in the rat impairs spatial learning performance in male offspring.

Pubescent (30 day old) male rats were maintained on an alcohol liquid diet containing 35% ethanol-derived calories (ALC) for 39 days or were pairfed an isocaloric control diet (PF). The concentration of alcohol in the diet was gradually increased to permit adaptation, then stabilized and then gradually tapered to prevent an alcohol withdrawal syndrome. Following a drug-free period (2 weeks), the males were mated with nontreated females. Offspring were evaluated on several developmental indices and on various learning/memory tasks to assess functional deficits in adulthood. Offspring sired by ALC-treated males did not differ from the offspring of PF males on several developmental parameters including body weights, when developmental landmarks appeared, or on tests of sensorimotor development. As adults, male offspring groups did not differ on tests of activity or on an object exploration/recognition task. However, male offspring of ALC-treated males demonstrated impaired acquisition performance (days and errors to criterion) on a win-shift spatial discrimination in an eight-arm radial maze and on a win-stay discrimination (days to criterion) conducted in a T-maze at a later age. The radial maze results were replicated in a subsequent experiment using different groups of rats.

Alcohol Drinking↗
PubMed2005

Choto-san, a Kampo formula, improves chronic cerebral hypoperfusion-induced spatial learning deficit via stimulation of muscarinic M1 receptor.

A recent double-blind and placebo-controlled study demonstrated a beneficial effect of Choto-san, a Kampo (traditional medicine of Japan) formula, on cognitive impairment in patients with vascular dementia. However, the neuronal mechanism underlying the therapeutic effects of this formula remains to be clarified. Using a chronic cerebral hypoperfusion model, we investigated the effect of Choto-san on cognitive dysfunction in mice to clarify its mechanism of actions. Chronic cerebral hypoperfusion was induced by permanent occlusion of both the common carotid arteries (2VO). Choto-san and Uncaria, a major constituent of Choto-san, caused an improvement in 2VO-induced learning deficits, whereas Uncaria-free Choto-san did not. The effects of Choto-san and Uncaria were blocked by pirenzepine, a selective muscarinic M1 antagonist. In a tube-dominance test, 2VO induced increased rates of assertive behavior in mice. 2VO mice administered Choto-san showed significantly reduced rates of assertive behavior compared to vehicle-treated controls, whereas Uncaria-free Choto-san and Uncaria had little effect on 2VO-induced assertive behavior. 2VO caused a significant decrease in the level of acetylcholine (ACh) contents in the brain, and the daily administration of Choto-san or Uncaria raised the ACh level to that in the sham-operated controls. These results suggest that Choto-san has an ameliorating effect on the spatial memory deficit caused by chronic hypoperfusion, and that the effect is mainly attributable to Uncaria. Moreover, it was suggested that the effects of Choto-san and Uncaria are at least partly mediated by stimulation of the muscarinic M1 receptor.

Acetylcholine↗
PubMed2004

Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus.

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calcium-calmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMff+) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAM-/-) mice. However, similar to the NCAM-/- mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMff+ mice. The deficit in LTP could be rescued by elevation of extracellular Ca2+ concentrations from 1.5 or 2.0 to 2.5 mm, suggesting an involvement of NCAM in regulation of Ca2+-dependent signaling during LTP. Contrary to the NCAM-/- mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMff+ as opposed to abnormal lamination in NCAM-/- mice. NCAMff+ mutants did not show general deficits in short- and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAM-/- mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.

Animals↗
PubMed1997

Effects of D-cycloserine and aniracetam on spatial learning in rats with entorhinal cortex lesions.

A great body of behavioural and neurophysiological evidence suggests that excitatory amino acids are involved in mechanisms of learning and memory. Moreover, degeneration of glutamatergic pathways may underlie the cognitive deficits seen in various disorders such as Alzheimer's dementia. As direct stimulation of glutamatergic receptors with agonists may increase the risk of toxicity and accelerate neuropathological changes, a more valid approach seems to be positive modulation of glutamatergic receptors that may reverse the symptoms with a lower risk of excitotoxic effects. Such a possibility offered by partial agonists of the strychnine-insensitive glycine site of the NMDA receptor (Gly-B site) or positive modulators of AMPA receptors, such as aniracetam. In the present study, the effects of d-cycloserine and aniracetam were tested in two animal models of cognitive deficits (entorhinal cortex lesion-induced deficits evaluated in the radial maze and scopolamine-induced amnesia evaluated in passive avoidance test). D-cycloserine (6 mg/kg, for 10 days) had no effect on spatial working memory deficit induced by entorhinal cortex lesions. It did, however, reverse scopolamine-induced deficits in the passive avoidance test when given acutely at the same dose. In contrast, aniracetam (50 mg/kg, for 10 days) produced beneficial effects in the radial maze test in rats with entorhinal cortex lesions, but given at the same dose acutely did not influence scopolamine-induced amnesia. The positive effect of d-cycloserine against scopolamine-induced amnesia may be probably related to the cholinergic-glutamatergic interaction in the hippocampus. The negative data obtained with d-cycloserine in the model of entorhinal cortex lesions-induced cognitive deficits could be taken as a hint that it is probably not suitable for the symptomatological therapy of Alzheimer's disease. The mechanism of positive action of aniracetam cannot be explained on the basis of AMPA receptor modulation, as the dose used (50 mg/kg) is well below that required for the effect at AMPA receptors. Other actions such as peripheral effects or modulation of metabotropic receptors seem more likely.

Animals↗
PubMed2005

Apolipoprotein E-deficient mice exhibit increased vulnerability to intermittent hypoxia-induced spatial learning deficits.

Exposure to intermittent hypoxia, such as occurs in sleep-disordered breathing, is associated with oxidative stress, cognitive impairments, and increased neuronal apoptosis in brain regions involved in learning and memory. Apolipoprotein E (ApoE) has been implicated in neurodegenerative disorders, and in vitro studies suggest that one of the functions of ApoE may be to confer protection from oxidant stress-induced neuronal cell loss. Therefore, we hypothesized that ApoE-deficient (ApoE-/-) mice would display increased cognitive impairments following intermittent hypoxia. Twenty-four young adult male mice (ApoE-/-) and 24 wild-type littermates (ApoE +/+) were exposed to 14 days of normoxia (room air; n=12 per group) or intermittent hypoxia (5.7% O2 alternating with 21% O2 every 90 seconds, 12 daylight hours per day; n=12 per group). Behavioral testing consisting of a standard place-training reference memory task in the water maze revealed that ApoE+/+ and ApoE-/- mice exposed to intermittent hypoxia were found to require significantly longer times (latency) and distances (pathlength) to locate the hidden platform (P < .005), compared to mice exposed to room air. However, only intermittent hypoxia-exposed ApoE-/- mice were impaired on the final two days of training (P < .03), as well as on measures of spatial bias conducted 24 hours after completion of training (P < .02). Furthermore, increased prostaglandin E2 and malondiadehyde concentrations were present in hippocampal brain tissues following intermittent hypoxia but were significantly higher in ApoE-/- mice (P < .01). Thus, decreased ApoE function is associated with increased susceptibility to neurocognitive dysfunction in a rodent model of sleep-disordered breathing and may underlie the increased prevalence of Apolipoprotein E4 in patients with sleep-disordered breathing.

Animals↗
PubMed1997

LTP and spatial learning--where to next?

Hebb suggested, in 1949, that memories could be stored by forming associative connections between neurons if the criterion for increasing the connection strength between them be that they were active simultaneously. Much attention has been devoted towards trying to determine a) if there is a physiological substrate of such a rule, and b) if so, whether the phenomenon participates in real-life memory formation. The discovery of the electrically induced increase in synaptic strength known as long-term potentiation (LTP), in the early 1970s, demonstrated that a neural version of the Hebb rule could be observed under laboratory conditions in the hippocampus, a structure important for some types of learning. However, a quarter of a century later, the evidence linking LTP to learning and memory is still contradictory. The purpose of the present article is to review and assess the types of approach that have been taken in trying to determine whether hippocampal synaptic plasticity participates in memory formation.

Animals↗
PubMed1981

Recovery of visual-spatial learning and memory in chronic alcoholics.

Administered the Memory-for-Designs Test and a verbal and visuospatial paired associate learning test to separate groups of alcoholics (N = 32) 3 and 11 weeks abstinent from alcohol and to a matched control group (N = 16). Alcoholics were not impaired in verbal learning. Alcoholics 3 weeks abstinent performed significantly less well than controls on all nonverbal tasks and less well than 11-weeks alcoholics on one nonverbal measure. No significant differences were found between 11-week alcoholics and controls. The results suggest that some recovery of function may occur in alcoholics after 10 weeks of abstinence. The data also support the hypothesis of impaired right hemisphere in alcoholics.

Alcoholism↗
PubMed1988

Experience during suckling alters later spatial learning.

These experiments explore the role of preweaning experience in learning during the juvenile period. Pups that had been reared with many nipples available reached criterion on an 8-arm radial maze in a few trials; conversely, pups reared with only a few nipples required 3 times the number of trials to reach criterion (Experiment 1). Pups that had been reared with relatively few nipples available rarely nipple-shifted, while those that had been reared with a particularly high density of nipples shifted more frequently (Expt 2). A rearing procedure was devised that allowed precise experimental control of all phases of the suckling experience (Expt 3). Allowing or preventing a single behavior, nipple-shifting, while holding all other variables constant, was sufficient to affect acquisition of the maze task. In Experiment 4, the specificity of the early experience for later tasks was explored using a variety of nonspatial, lever-pressing operants. Rearing condition did not affect acquisition of a lever-pressing operant or of a visual discrimination task. However, pups reared with a high density of nipples responded at higher rates to a variable interval schedule and were more resistant to extinction. The possibility that strategy, rather than learning ability, was affected by rearing condition was assessed using a 2-arm maze task that was structured to present an optimal strategy of either win-shift or win-stay (Expt 5). The ease with which rats acquired the win-stay task was unaffected by rearing condition; all groups performed at about chance levels. However, pups reared with many nipples more readily acquired the win-shift task.

Animals↗
PubMed1995

Ontogeny of orientation and spatial learning on the radial maze in mice.

The development of the orientation capacities of C57BL/6 mice has been studied on the radial maze in several procedures allowed to dissociate the different types of cues used by the mouse for solving the task with two intersession delays (2 and 24 hr). The results of the first two studies show that performance is independent of intersession delay regardless of the age of the subject. Mice as early as 23 days old obtain good performances when they can develop an algorithmic strategy or when they dispose of both proximal and distal cues during learning. At 37 days of age, however, mice can efficiently solve the radial maze task with distal cues alone. However, in the third experiment, 23-day-old mice were able to use distal cues for orientation at the end of the learning session if, at the onset, they also had access to proximal cues. These results suggest that, on weaning, mice use several types of information for task performance and that, as they mature, they turn more often to distal cues for orientation.

Aging↗